Pasithea Therapeutics Corp. (KTTA) Earnings Call Transcript & Summary

Hello, everyone, and welcome to Oppenheimer's 36th Annual Life Sciences Conference. I'm Jay Olson, one of the biotech analysts here at Oppenheimer, and it's a pleasure to welcome you to our discussion with Pasithea Therapeutics. And it's an honor to introduce Tiago Reis Marques, the CEO of Pasithea. Thank you so much, Tiago, for joining us here today. I'll turn it over to you.

Thank you so much, Jay. Thank you as well to the Oppenheimer team for inviting us to be in this conference. It's really a pleasure to have the chance to introduce the company and our program. Having said this, and before starting the presentation, just asking everyone to pay attention to our company disclaimer as it contains some forward-looking information. As part of the disclaimer, I also want to disclaim that I've been under the weather the past few days. And so I apologize to everyone for my voice is still not totally recovered. Having said this, today, I'm highlighting here on this slide why we consider Pasithea to be a very compelling story. I'm going to discuss today our lead program, Basel IV, the first macrocyclic MEK inhibitor to be advanced into clinical trials. And due to, its properties, I'm going to also show some data supporting a differentiated profile, particularly our safety, PK and some early signs of monotherapy efficacy. I'm going to be covering also our main indication that is the neurofibromas that are associated with disease called neurofibromatosis type 1, in particular, discussing the plexiform neurofibromas, as well as cutaneous neurofibroma. And then the large market opportunity that it constitutes. We -- this is a very large TAM. Currently, MEK inhibitor in NF1 are only -- and we only have data for MEK inhibitor in pediatric population with worldwide sales of approximately $0.5 billion annually, but we consider that the TAM is much larger. And when we consider the opportunity in cutaneous, it can be a very, very interesting opportunity. We -- although all our focus is in our PAS-004 program, we also have other programs, particularly one in schizophrenia, PAS-001. But as I mentioned, currently, all our attention and capital is devoted to advance PAS-004. We currently have 2 clinical trials ongoing, a dose escalation trial in advanced cancer, and we hope to report data at ASCO, an update on the trial and also a Phase Ib study in the NF1 population, and we're going to have -- going to report data on the second half of this year. So -- now I'm going to discuss PAS-004, our next-generation MEK inhibitor. Giving you a brief overview of what MEK inhibitors do, MEK inhibitors target one of the proteins in the MAPK pathway. That is a very important pathway for cell survival and proliferation. It's constituted by a chain of proteins, TRAS, RAF, MEK and ERK that when abnormally activated lead to the formation and progression of tumors. And these mutations in this MAPK pathway have been described in many different types of cancers. But also there's been mutations in RASopathies. And in NF1, there's a mutation in the NF1 gene that -- that encodes for protein, neurofibromin that is a negative regulator of RAS. So when to -- when this protein is not functioning, the MEK pathway is hyperactivated. A MEK inhibitor block MEK -- inhibit MEK and block the phosphorylation of ERK. As mentioned initially, currently in NF1 alone, we have data from one of the MEK inhibitors. There are currently 2 MEK inhibitors approved for the treatment of plexiform neurofibromas in NF1 both approved very recently for pediatric and other population. But until very recently, there was only selumetinib approved for the pediatric population and doing annually approximately $500 million in sales. So talking about NF1 that is a genetic disorder with a complex phenotypic presentation, NF1 patients can develop neurofibromas that are non-malignant tumors derived from [ tissue, adenoma ] cells. Some of these tumors are present around and grow around the large nerves in our body. And these are called the plexiform neurofibroma. They are present since birth. They grow at a slow rate of 2% to 3% a year. And at some point, as you can see here in the image, they will either cause deformities or they will compress structures or because they wrap around the nerve, they will lead to motor dysfunction or sensory dysfunction. There's -- until the approval of MEK inhibitors, the only available treatment was surgery. As you can imagine, doing a surgery of a tumor that grows around a nerve is very complex, very difficult to remove without causing serious side effects. These plexiform neurofibromas also have a malignant potential. Not all patients with NF1 develop plexiform neurofibroma. NF1 is a genetic disorder that affects 1 in every 3,000 newborns, meaning that there are currently around 115,000 patients in the U.S. alone living with NF1. Around 30% to 50% develop plexiform neurofibroma. So let's say, around 50,000 patients in the U.S. alone. And for these indications, there are 2 MEK inhibitors approved, selumetinib marketed by AstraZeneca and mirdametinib that has been developed by SpringWorks and now since its acquisition by Merck KGaA is sold by this company. But then 100% of patients develop cutaneous neurofibroma. They are also neurofibromas and they arise from the nerve terminals that we have all over our body. And they show up as skin bumps. They typically grow in numbers. They can even grow to thousands, as you can see in the image. Some patients have only some dozens, but -- of course, this cause a huge impact in the patient quality of life. They can also cause pain, pruritus and irritation. And there is no approved treatment for this indication. So now let's focus on the current treatment landscape with 2 drugs approved. Both selumetinib and mirdametinib are drugs that are dosed twice a day. They have a short half-life. They typically tend to take 7 to 8 months to generate a response. But what is really evident, and here we're bringing in-label data is the suboptimal profile leading to many patients discontinuing or having those reductions or interruptions. And if you look to the safety profile, you're going to see that patients present with many adverse events, particularly rash that can as high as 80% to 90% GI tox also somewhere around 50% to 60% and GI tox with nausea, vomiting and diarrhea. CK increase, typically symptomatic, around 50% of the patients and then ocular and cardio tox around 20% of the patients. This is, of course, what is on label. But if we look to the severity of these AEs, we know that around 20% of patients develop Grade 3s. And we also know that somewhere between -- and this is data from the clinical trials, the Phase II clinical trials, registrational trials that led to approval that approximately 20% of patients end up discontinuing to drug over the first 2 years of treatment. So definitely, there's a huge room to improve in the safety profile of a MEK inhibitor. So this is what we're trying to achieve with PAS-004. And our drug fit the sweet spot between efficacy, safety and also a differentiated PK profile. And going to show you in the subsequent slides data that support this claim. First, let's talk about how PAS-004 differentiates from other drugs. PAS-004 is the first macrocyclic drug, and you can see this ring-like structure that confer the macrocyclic structure versus cyclic structures of other MEK inhibitors. It was -- and because of the conformational rigidity of these molecules of macrocyclic structure molecules, they are typically highly selective with a reduced off-target effects. There are also molecules that typically have a very long half-life and also improve oral bioavailability. When designing PAS-004, we also took a very attention to removal of metabolic and stable groups such as primary alcohols that other MEK inhibitors present. And this allows us to reduce the potential for having any active metabolites that are present with other MEK inhibitors. And now talking about conceptually what we think is our biggest differentiator versus existing MEK inhibitors. The 2 approved MEK inhibitors for NF1, they have very short half-life, as mentioned before, AstraZeneca -- between AstraZeneca and mirdametinib, their half-life is between 6 to 7.5 hours. And with this short half-life, what typically occurs is that the drug is immediately absorbed, reach a very high Cmax and then the drug concentrations drop, and drop below [ therapeutic ] level. And this pattern, this pulsatile pattern happens every 12 hours. So it's impossible to titrate the pathway with drugs with such a short half-life. On contrary, with a very long half-life such as the one we've seen with PAS-004, it allow us to -- once steady state levels are achieved to keep a constant inhibition with Cmax to Cmin ratio below -- in the case of PAS-004 below 2, with the drug even at C trough being above the therapeutic level and with Cmax below what we consider a toxic level. And the ability to titrate the pathway is very relevant for an indication such as NF1. So currently, and before presenting our human data, we have, as previously mentioned, 2 ongoing clinical trials. This is our Phase I/Ib clinical trial in NF1, and it consists of a Part A modified 3+3 dose escalation design and a Part B of dose expansion. In this Part A, we're testing 4 different dose regimens for 12 and 18 milligram, and we're going to select 2 doses for a dose expansion. Patients in Part A are followed approximately for at least 6 months, but patients will continue on treatment even after the 6 months. So we're going to have data on both the plexiform neurofibroma and on the cutaneous neurofibroma volume by year-end. And after 2027, we're going to select 2 doses for dose expansion, and we're going to select a recommended Phase II dose for a registrational trial. We're currently conducting this trial in 5 different centers, 1 in the U.S., 2 in Australia and 2 in South Korea. Our dose escalation trial in advanced cancer patients with mutations in the MAPK pathway is a 3+3 study design study, and we're testing our drug in the capsule formulation in 8 different cohorts. We have now data in all cohorts. We have completed the 8 cohorts. And the main objective of this trial is to evaluate the safety as well as the PK/PD and some preliminary anticancer activity. And now let's look to the human data. On the left screen, you're going to see an overlap between our PK profile at the 37-milligram capsule dose and to mirdametinib published trial at the approved drug for NF1, 4-milligram BID. As you can see by the mirdametinib profile, it's -- the ratio between Cmax/Cmin is approximately 10, similar to selumetinib. And while PAS-004 show a very flat PK profile, if you look to the data on the table below, you're going to -- I want everyone to pay attention not only to our Cmax, but particularly to our Cmin. Our Cmin is much significantly higher than the C trough or Cmin of mirdametinib and selumetinib. And at these dose levels, the drug is still above the IC50 still an effective and therapeutic dose. So with this profile, we managed to keep the pathway continuously inhibit with a ratio between Cmax and Cmin below 2, actually around 1.5. Our drug, PAS-004 is less potent than mirdametinib, but more potent than selumetinib. And here is the overlap between PAS-004 at 37 milligram and approved dose of NF1. Another thing to pay attention is with this very flat PK, what we can achieve is very high exposures. And I will highlight the exposures because exposure matter as they correlate with treatment response in NF1. So at the 37-milligram dose, we're achieving exposures that are almost as high as the exposures of selumetinib. Here are some more data of our PK at multiple dose cohorts. As you can see, a very flat PK dose proportionality -- and with selumetinib, and this is data published by AstraZeneca, you see the [ variable ] PK profile and also the existence of -- and there is a matter of selumetinib, that is an active metabolite that can, of course, impact on the PK and on the safety of this drug. At the highest dose tested, we model these doses to be at or above the IC90. Bringing again, attention to exposure. This is data published by mirdametinib, where they explore relationships between treatment response in NF1 and the PK data. And what they've seen is that there is a positive relationship between treatment response and exposure. So every patient that responded with NF1, they have an AUC at -- from 0 to 12 hours higher than 600 nanograms. So if you multiply this 2, that's approximately 1,200. At the 37-milligram capsule, we're getting an exposure that is very, very high and both with capsules and also with tablets. And again, what matters in NF1 is not how high your Cmax goes, but really how high your exposure is. So this supports the fact that with a very long half-life and very large AUC, we might see also treatment response at these dose levels. We have efficacy data. So far, we only presented in our advanced cancer study. Monotherapy with MEK inhibitors in advanced cancer is limited. But we know and so far, we have efficacy, well, 22 efficacy available patients. And we know that certain mutations in the MAPK pathway are more sensitive to monotherapy MEK inhibitor in advanced cancer, typically MEK inhibitors are paired with a BRAF inhibitor. When we specifically look to patients with BRAF mutations such as V600E mutations, what we see is approximately 70% of patients achieved stable disease, so a disease control rate of 70%. And patients that remain on trial for many, many cycles with multiple stable disease scans along the way. Now let's look to our AE profile. This is the profile at different dose cohorts. We haven't yet disclosed the safety profile of our cohort 8 45-milligram capsules. So what we're seeing here is data up to Cohort 7 during the DLT period. And what you'll see is that we have GI tox such as vomiting, nausea and diarrhea below -- in less than 20% of the patients, also single-digit number in rash and fatigue and CK increase also in a limited number of patients. Of course, this is a dose escalation trial. Some of the patients in initial cohorts were those at doses that are subtherapeutic. So we need to take this data when we compare to existing on-label safety profile of AEs. But so far, even at the highest dose cohort tested, we're seeing a significantly improved safety profile. And when we look to mirdametinib advanced cancer study, so we're comparing our advanced cancer study with mirdametinib advanced cancer study, where they go from 1 milligram to 30-milligram BID at they approved dose for NF1 is the 4 milligram, as you can see here on green. When you look to the safety profile at even the lower dose of 2 milligram or 1 milligram, you're going to see that 50% of patients present with diarrhea, 75% with nausea. So we already in dose escalation studies of other MEKs, we are seeing AEs even at the lowest dose tested. So this supports the fact that what I've shown you before is not only the fact that we're dosing low is due to the fact that we're not getting to very high Cmax completely blocking the pathway and leading to safety profile. This is our program time lines as we're continuing our Phase I study in solid tumors. We're going to provide an update on the safety PK and efficacy at ASCO this year. And for the adult NF1 patients, we're going to present data on the Part A of the study by the second half of this year. We're also planning and start working into moving our drug into the pediatric population with ultimate goal to start a registrational trial, both in adult and pediatric patient population by 2028. Again, just highlighting that what we're going to show in the second half of this year is not only data in plexiform neurofibroma, but also into cutaneous neurofibroma where currently there is no drug approved. We're also assessing other potential opportunities in the space, particularly looking to other RASopathies such as Noonan syndrome. And we have an investigator-led trial that recently -- that is about to start in ALS. Finally, focusing on our intellectual property, we have currently a composition of matter patent issue until September 2032 with an extension to 2037. But we filed in January 2024, a new composition of method, method based on the identification of a crystalline form, and we anticipate that this will provide patent protection until 2045. We also have orphan exclusivity for NF1, and we're pursuing multiple patent extension strategies. In November of last year, we completed a financing with a very strong group of investors, and we raised $60 million. So we have disclosed by year-end approximately cash balance of $60 million. That will allow us to run our company until at least the first half of 2028. Currently, we have approximately 88 million shares outstanding. Having said this, I hope that everyone considers Pasithea a compelling investment opportunity. And of course, we'll be free and available to discuss any of this data with everyone. Thank you so much for your attention.

Thank you, Tiago. I don't know if maybe we have time for 1 or 2 questions or so. Maybe starting with -- could you comment on the brain penetration ability for 004? And do you think that brain penetrant is important for treating NF1?

Not for treating NF1. Actually, mirdametinib is very brain penetrant, and they've been -- they suffer from ocular tox. And that's why in NF1, the drug, mirdametinib is dosed 3 weeks on, 1 week off. We haven't yet assessed the brain penetration of PAS-004, and we're very excited with the opportunity to test PAS-004 in ALS patients because we're going to be assessing the PAS-004 concentrations into CSF.

Okay. Great. Well, we look forward to that. And then maybe if you could comment briefly on the tolerability profile for 004. It looks like it has very favorable therapeutic index so far. And with regards to tolerability, will you be collecting any patient-centric measures like quality of life?

In NF1, yes, we're collecting that, not in the advanced cancer study. And what we can comment is really we haven't seen any Grade 3 AE. We haven't seen any dose discontinuation. All patients remain on trial. We haven't seen any DLT. And of course, we have the convenience of our drug being dosed once a day. We still haven't conducted food effect studies. So our drug is still taken fasted. And we know that once taken with food, MEK inhibitors can flatten the PK profile and lead even to a better safety profile. So all of this, all of the existing data suggest that PAS-004 is a very tolerable drug. Of course, as more data emerge, we will be hoping to continue to see the same profile.

Okay. Perfect. We'll wrap things up there. Thank you so much, Tiago, for joining us here today and bringing us up to speed on all the impressive work you're doing at Pasithea.

Thank you so much.

Our pleasure. Thanks, everyone, for joining us.